Quinazolines, being one type of nitrogenous heterocycles, have been identified with a variety type of biological activities, such as analgesic [1 (Note: bracketed numerals used herein relate to listed references appearing below within the Detailed Description Of Illustrative Embodiments)], antibacterial [2], antibiotic [1(b)], anticonvulsant [1(a),2(b),3], antidepressant [4], anti-inflammatory [1(a), 3, 5], anti-hypertensive [1(b), 3], antimalarial [2(a), 6], antineoplastic [2(a)], antitumoral [1(b), 7] as well as diuretic [1(b), 3], genotoxic [8], hypoglycemic [1(b)], narcotic [1(b)], sedative activities [1(b)] etc. Thus, the quinazoline derivatives have been applied as inhibitors for dihydrofolate reductase [2(a), 6], epidermal growth factor receptor [3, 7, 9], NADH-quinone reductase [10], TNF-α production [11], as well as T cell proliferation [11-12]. As a result, many pharmaceutical compounds containing quinazoline moiety have been widely applied for medicines.
For example, Alfuzosin is used in men to treat symptoms of an enlarged prostate [13], so-called benign prostatic hyperplasia [14]. Doxazosin, with structure and activity similar to Alfuzosin, is also used in men to treat the symptoms of an enlarged prostate [13-14]. Gefitinib is used to treat non-small cell lung cancer in people who have already been treated with other chemotherapy medications whereas whose conditions have not been improved or even become worse [9(a), 15]. Erlotinib, with a structure similar to Getifinib, is also used to treat non-small cell lung cancer that has spread to the nearby tissues or to other parts of the body in patients who have already been treated with at least one other chemotherapy medication without obvious improvement [16]. Lapatinib is used to treat a certain type of advanced breast cancer in people who have already been treated with other chemotherapy medications [17].
In comparison, perimidine derivatives, with an extended aromatic system larger than quinazolines, have also been identified with a variety type of biological activities, such as antibacterial and antifungal activity [18], cytotoxic effect and in vivo immunosuppressant and immunostimulant activity [19], and have been applied as antagonists for nonpeptide corticotropin releasing factor (CRF) receptor [20]. In addition, perimidines usually absorb light of longer wavelength that could be stretched to the range of visible light and even to near-infrared range [21]. Thus, perimidines may appear in different colors, depending on the conjugated aromatic system as well as the functional groups they carry. As a result, perimidines have been developed as colorants, dyes and pigments [22].
Due to the wide applications of quinazolines as well as perimidines, a variety type of synthetic or preparative methods have been developed to make these type of heterocycles, according to the available starting materials and the structures of final products with different functional group distributions. Among these synthetic or preparative methods for quinazoline derivatives, a large portion of methods are focused on the introduction of the desired functional group into the existing quinazoline core-structure, which are not related to the current disclosure. In addition, even though there are still many synthetic methods for quinazoline derivatives that have a functional group attached to position 4 of quinazoline moiety through a heteroatom, such as oxygen, nitrogen, sulfur, etc., or with a functional group as simple as hydroxyl (OH), amino (NH2), or halogen (F, Cl, Br, I), these methods are in fact not related to the current disclosure either.
There is a need for a general, simple and direct method for the preparation and/or manufacturing of quinazoline derivatives that carry one substituent at position 4 of quinazoline ring via a carbon atom attachment, and may contain other functional groups at the rest positions of quinazoline rings, except for position 2 of the quinazoline ring where no other functional group rather than hydrogen is attached. This direct method for the preparation of quinazoline derivatives also includes or is applicable to the preparation and/or manufacturing of even largely fused quinazoline derivatives that include perimidines, anthrapyrimidine-7-one, anthra[1,9:5,10]dipyrimidine and benzo[e]pyrimido[4,5,6-gh]pyrimidine when different 1-amino-9H-fluoren-9-ones, aminoanthraquinones are used as the starting materials. Likewise, only those methods for the preparation of perimidines, such as anthrapyrimidine-7-ones, anthra[1,9:5,10]dipyrimidines and benzo[e]pyrimido[4,5,6-gh]pyrimidines, which are closely related to the disclosed method will be compared below.
The preparation of quinazoline derivatives with a carbon-attached substituent at position 4 may be classified into several groups as described below, using 4-phenylquinazoline as in the following examples:
a) The preparation of 4-phenylquinazolines from an N-benzylideneaniline type of Schiff base that is formed from aniline and benzaldehyde, as shown in the reaction between p-chloro-(α-chlorobenzylidene)aniline and benzonitrile in 1,4-dichlorobenzene at 140° C. in the presence of AlBr3 that afforded 69% of 6-chloro-2,4-diphenylquinazoline [23], and the reaction between N-[o-(triphenylphosphoranylideneamino)benzylidene]-p-toluidine and p-nitrobenzaldehyde when refluxed in xylene for 12 hours that gave 70% of 6-methyl-4-p-nitrophenyl-2-phenylquinazoline [24]. The latter reaction would afford dihydroquinazolines as well if other benzaldehydes rather than p-nitrobenzaldehyde are used. In addition, the reaction between 3,4-diphenyl-1,2,4-oxadiazol-5(4H)-one and benzylideneaniline also afforded 2,4-diphenylquinazoline [25];
b) The preparation of 4-phenylquinazolines from amidobenzenes or benzonitriles, as shown in the reaction when p-chloropivalamidobenzene was dilithiated with n-BuLi followed by the addition of o-fluorobenzonitrile to give 57% of 2-t-butyl-6-chloro-4-o-fluorophenylquinazoline [26], and the treatment of o-aminobenzonitrile with phenylmagnesium halide from which the resulting intermediate 2-H2NC6H4C(Ph)=N− then cyclized with carbonyl compounds (e.g., acid chlorides, anhydrides, formates) to give 4-phenyl-quinazolines [27]. Alternatively, the reaction between benzanilides and benzonitriles in the presence of PCl5 and AlCl3 in PhNO2 at 120-150° C. also afforded 2,4-diphenylquinazoline [28];
c) The reaction between benzenediazonium salt and benzonitrile, as shown in the reaction between o-benzylbenzenediazonium tetrafluoroborate and benzonitrile that gave 53% of 8-benzyl-2,4-diphenylquinazoline [29];
d) The conversion of benzo[e][1,4]diazepine derivatives into 4-phenyl-quinazolines, such as the refluxing of 3-hydroxy-5-phenyl-3H-1,4-benzodiazepin-2(1H)-one in AcOH to give 35% of 4-phenyl-2-quinazolinecarbaldehyde [30], thermolysis of 7-chloro-3-(2-methylimidazol-1-yl)-5-phenyl-3H-1,4-benzodiazepin-2-amine in 50% H2SO4 that afforded about 15% of 6-chloro-4-phenyl-2-quinazolinecarbaldehyde [31], thermolysis of 7-bromo-3-hydroxy-5-pyridin-2′-yl-3H-1,4-benzodiazepin-2(1H)-one at 220° C. to give 6-bromo-4-pyridin-2′-yl-2-quinazolinecarbaldehyde [32], sublimation of 7-chloro-5-phenyl-1,3-dihydro-2,1,4-benzothiadiazepine 2,2,4-trioxide at 160° C. under vacuum (at 10−3 mmHg) to give 6-chloro-4-phenylquinazoline [33], acidic hydrolysis of 8-chloro-6-phenyl-3,4-dihydro-1,5-benzodiazocin-2-amine in refluxing methanolic hydrogen chloride for 2.5 hours to afford 53% of 2-α-aminoethyl-6-chloro-4-phenylquinazoline [34], treatment of 8-chloro-3-methyl-6-phenyl-3H-4,1,5-benzoxadiazocin-2(1H)-one with sodium methoxide for 20 hours to yield 50% of 2-acetyl-6-chloro-4-phenylquinazoline [35], oxidation of N-methyl-7-nitro-5-phenyl-1H-1,4-benzodiazepine-3-carboxamide with CrO3 in AcOH to give 29% of N-methyl-6-nitro-4-phenyl-2-quinazolinecarboxamide [36], and hydrogenation of 8-chloro-6-phenyl-3H-4,1,5-benzoxadiazocin-2(1H)-one oxime over Raney-nickel to afford 50% of 6-chloro-2-hydroxymethyl-4-phenylquinazoline [37];
e) Thermolysis of 1,3,6-triphenyl-1,4-dihydro-1,2,4,5-tetrazine at 200° C. to a mixture of three components that included 2,4-diphenylquinazoline [38];
f) The reaction between 3-phenylbenzo[c]isoxazole and 5-methoxy-3-phenyl-2,4-imidazolidinedione in refluxing dioxane containing TiCl4 as catalyst to give 82% of 4,N-diphenyl-2-quinazolinecarboxamide [39];
g) Isomerization of 7-chloro-5-hydroxy-5-phenyl-1,2,3,5-tetrahydropyrrolo[1,2-a]-quinazolin-1-one into 2-α-carboxyethyl-6-chloro-4-phenylquinazoline in ˜45% yield under basic condition [40];
h) The conversion of benzotriazene derivatives into 4-phenyl quinazolines, such as the transformation of 1,2-diaryl-2-(benzotriazol-1-yl)enamines prepared from lithiated (α-arylbenzotriazol-1-yl)methane and nitriles to afford 2,4-arylquinazolines, and the reaction between 2-(benzotriazol-1-yl)-1,2-diphenylethanone and formamide at 150° C. to afford 50% of 2,4-diphenylquinazoline [41]; and
i) the treatment of 1-amino-4-methyl-9H-thioxanthen-9-one 10,10-dioxide with formic acid-formamide at 180° C. for 3 hours to give a mixture of products from which 6-methyl-4-phenylquinazoline was isolated in low yield [42].
Although these known methods listed from a) to i) all lead to the formation of 4-phenylquinazolines, they are quite different from the presently disclosed method, because the cited methods mentioned above all afford 4-substituted quinazolines with an additional functional group at position 2 through a carbon-carbon attachment for which the removal of such group might prove difficult to accomplish.
Only the following several methods are of a kind of similarity to the presently disclosed method, to an extent, that all use 2-aminobenzophenone as the starting material. These similar synthetic methods include the reaction between 2-aminobenzophenone and ethyl carbamate and further treatment with phosphoryl trichloride [43], thermal reaction between 2-aminobenzophenone and formamide [44], the reaction between hydroxyglycine and 2-aminobenzophenones to give 1,2-dihydro-4-phenylquinazoline-2-carboxylic acids which is then converted into the corresponding quinazoline derivatives via air oxidation [45], and the treatment of 2-aminobenzophenone with urotropine and ethyl bromoacetate in alcohol to form a mixture of 4-phenylquinazoline and 4-phenyl-1,2-dihydroquinazoline [46].
For comparison, several methods have been developed for the preparation of aromatically-fused perimidine derivatives, including but not limited to anthrapyrimidine-7-ones, anthra[1,9:5,10]dipyrimidines and benzo[e]pyrimido-[4,5,6-gh]pyrimidines starting from aminoanthraquinones. Examples from such methods include the following:
a) a mixture of 1:2 ratio of 1-N-acetylaminoanthraquinone and phenol when treated with ammonia gas at a pressure of 5 atm at 125-130° C. afforded 2-methyl-1,9-anthrapyrimidine [47];
b) the thermal treatment of 1,5-diaminoanthraquinone-2-sulfonic acid with formamide followed by more than 10 times of 25% aqueous ammonia at 195-200° C. afforded diamino-1,9-anthrapyrimidine [48];
c) the reaction of 5-amino-4′-benzoylamino-1,1′-anthrimidecarbazole with 5 equivalents (by weight) of formamide and 10 equivalents of phenol for several hours formed 4′-benzoylamino-5,10-pyrimidino-1,1′-anthrimidcarbazole [49];
d) treatment of 7.8 parts of N,N-dimethyl-N′-[anthraquinoyl-(1)]-formamidinium chloride with 7.8 parts of ammonium acetate in 100 parts of glycol methyl monoether at 20° C. for 30 minutes gave 5.2 parts of 1,9-anthrapyrimidine, which could also be prepared by the treatment of 15.7 parts of N,N-dimethyl-N′-[anthraquinoyl-(1)]-formamidinium chloride with 14.4 parts of ammonium carbonate in 300 parts of methanol at 20° C. for 30 minutes which gave 10.6 parts of 1,9-anthrapyrimidine [50];
e) treatment of 50 parts of 1-dimethylformamidino-4-bromoanthraquinon-2-sulfonic acid with 25 parts (by weight) of an ammonium acetate in 800 parts of glycol monomethyl ether at 50° C. for 4 hours afforded 28 parts of 4-bromo-anthrapyrimidin-2-sulfonic acid [51];
f) the reaction between 19.5 parts of 1,5-dihydroxy-4-propionylamino-8-aminoanthraquinone and 9.2 parts of dimethylformamide in 240 parts of chlorobenzene in the presence of 10.7 parts of thionyl chloride for 2 hours at 70° C., and the resulting product extracted with acetone was then treated with 30 parts of ammonium acetate in 250 parts of ethyleneglycol monomethyl ether at 75° C. for 4 hours to afford 18.2 parts of 1,5-dihydroxy-4-propionylamino-8,10-anthrapyrimidine [52]; and
g) the reaction between 42.2 grams of 1,4-diamino-2,3-diphenoxy-anthraquinone and 31 grams of benzonitrile in 150 grams of trichlorobenzene in the presence of 34.4 grams of p-TsOH at 190° C. for 5-6 hours afforded 46.6 grams of 6-amino-2-phenyl-4,5-diphenoxy-anthrapyrimidine [53].